NGAL in AKI and cirrhosis—Ready for prime time?
Authors: Andrew S. Allegretti
Journal: Hepatology (2022)

Acute kidney injury (AKI) is a common complication of decompensated cirrhosis, and acute‐on‐chronic liver failure (ACLF) and is associated with a dismal mortality rate.1 Clinicians must promptly and accurately identify the type of AKI in order to guide management, and in cases of hepatorenal syndrome (HRS‐AKI), prescribe vasoconstrictors like telripressin to reverse the functional injury related to decreased circulating volume.1 Distinguishing the structural kidney damage seen in acute tubular necrosis (ATN) from functional injury like prerenal AKI and HRS‐AKI is a challenge in itself. Although there is no widely available diagnostic test that can do this on its own, the most recent set of guidelines from the International Ascites Club specifically calls for further study of urinary biomarkers of tubular injury to aid in the diagnosis of HRS‐AKI.1 In particular, urinary neutrophil gelatinase–associated lipocalin (NGAL) has emerged as a leading candidate to fill this urgent clinical need.2 In their retrospective cohort study, Gambino and Piano et al. assessed 90‐day outcomes of 162 consecutive adult patients who were hospitalized with AKI and cirrhosis at a single center in Italy.3 Their aim was to assess urinary NGAL's performance in (a) differentiating ATN from functional AKI in cirrhosis (i.e., prerenal AKI and HRS‐AKI), (b) predicting short‐term mortality, and (c) predicting response to terlipressin treatment among those with HRS‐AKI. Urinary NGAL was used as part of routine clinical care during the study period, and their population demographics were similar to those published in prior studies,4,5 making this study an excellent snapshot of the "real clinical practice" performance of a test like NGAL. The authors demonstrated urinary NGAL's excellent ability to distinguish ATN (1162 ng/ml) from non‐ATN AKI (87, 111, and 109 ng/ml for prerenal AKI, HRS‐AKI and mixed AKI, respectively; p < 0.001). Using an optimal cutoff point of >220 ng/ml as the diagnostic threshold for ATN, the test performed well, with a sensitivity of 89% and specificity of 78% and an overall area under the curve (AUC) of 0.854. They also demonstrated that elevated NGAL was associated with 90‐day mortality in adjusted and unadjusted Cox models. However, their most important finding was in their subgroup analysis of 64 terlipressin‐treated patients with HRS‐AKI. This group had a 59% overall treatment response rate, and by applying their previously derived optimal cutoff point of 220 mg/ml, NGAL could further improve prediction of terlipressin response (70% for <220 mg/ml vs. 33% for >220 mg/ml; p = 0.015). This finding remained true after adjusting for multiple factors, including serum creatinine at the time of terlipressin initiation, which is a known predictor of response to terlipressin.6,7 Overall, this important paper affirms that NGAL has a role in the diagnosis and prognosis of AKI in cirrhosis.2 Interestingly, the optimal cutoff point to diagnose ATN (220 mg/ml) and the test performance (AUC 0.854) identified in this paper were remarkably similar to two recent similar single‐center studies out of Barcelona, Spain4 (cutoff point 220 mcg/g creatinine; AUC 0.87) and Boston, Massachusetts5 (cutoff point 244 mcg/g creatinine; AUC 0.762). Although the latter two studies corrected urinary NGAL for urine creatinine and used different assays (Bioporto, compared with Abbott in this manuscript), the consistency of results across different studies (and countries) suggests that NGAL has favorable and reliable performance across platforms and different cirrhotic populations.8 Distinguishing ATN from functional injury like HRS‐AKI has major treatment implications in personalizing the care of patients with cirrhosis. Prerenal AKI is typically managed with volume resuscitation; ATN is managed supportively (typically with less volume); and HRS warrants vasoconstrictor therapy and ongoing albumin infusion. Given the recent Food and Drug Administration (FDA) approval of terlipressin for the treatment of HRS in North America,9 the potential added value of NGAL to our existing diagnostic tool chest has never been higher. This study is the first to demonstrate that not only does NGAL correctly identify HRS‐AKI, but also predicts treatment response to terlipressin. Compared with midodrine and octreotide, which is commonly used as an off‐label treatment for HRS in which alternative therapies are not available, telripressin is a more potent splanchnic vasoconstrictor, leading to both higher efficacy, but also a potentially higher side‐effect profile.6,10 In particular, terlipressin's new FDA label carries a boxed warning, advising caution in patients at high risk for respiratory failure, such as patients with pre‐existing volume overload or ACLF grade 3 (invoking three or more organ system failures), as well as a limitation of use noting that patients with serum creatinine >5 mg/dl are unlikely to benefit.11 Although there is great anticipation for terlipressin's availability in North America, this medication needs to be used judiciously. A biomarker like NGAL that can further risk‐stratify a heterogeneous population like HRS‐AKI and enrich for higher rates of treatment success has immediate and practical clinical value. The mechanism of why NGAL would predict response to terlipressin is relatively straightforward. In order for HRS‐AKI to be successfully reversed, three components need to be present. First, renal perfusion/effective circulating volume needs to be restored on a macrovascular level—this is the job of splanchnic vasoconstrictors and colloids like albumin. Second, the renal microcirculation of the smaller arterioles and glomerular capillary loops must be intact. This can be disrupted by acute inflammation, which is increasingly being identified as a part of the pathogenesis of HRS‐AKI and ACLF in general.2,12 Finally, the renal tubules must be intact so that sodium, water, and other solutes can be properly cleared once renal perfusion is restored by medical therapies. As a sensitive marker of proximal tubular function, lower urinary NGAL levels can identify patients with HRS‐AKI who have intact renal tubular infrastructure, and thus would be poised to improve kidney function if the other two features are also met. Interestingly, of the 35 patients in this study identified as having a "mixed" etiology of AKI, 11 received terlipressin, and only 3 of 11 (27%) responded to treatment. Although this subgroup is too small to evaluate NGAL's performance in predicting response, it does suggest that the existing diagnostic criteria for HRS‐AKI remain crucial in establishing a patient's appropriateness for vasoconstrictors like terlipressin. A single test like NGAL is best used as an adjunct to current guideline definitions of HRS‐AKI, rather than a replacement for them. It may be that a panel of objective biomarkers becomes available in the future that covers all three of the domains, but for now, the diagnosis HRS‐AKI requires a nuanced and attentive clinical approach. It is worth remembering that the performance of any test is only as good as the population in which it is applied. This population had a high representation of patients with HRS‐AKI (39.5%) and patients with early AKI stage (creatinine at time of AKI was 164 μmol/L [1.85 mg/dl]; 55.6% had stage I AKI), leading to a relatively high treatment response rate (59%), which in turn can influence test performance and optimal cutoff point levels. Similarly, their definition of ATN, which used a set of objective findings indicative of high degrees of tubular damage, likely did not capture patients with mild tubular injury that may still exist on the HRS‐AKI spectrum. This population, in whom the cause of injury may be "mixed" or overlapping between HRS‐AKI and ATN, are the most challenging to diagnosis and treat, so the performance of tests like NGAL would be of particular value here. Future studies should consider evaluating NGAL against other established tests of tubular function, such as fractional excretion of sodium, and even urine protein/creatinine ratios, to further interrogate this overlap group. Thinking forward, there are several areas left to investigate around NGAL's role in AKI in cirrhosis. These data showing how NGAL predicts response to terlipressin should be externally validated in prospective studies. Further work is needed to establish the optimal cutoff point both for diagnosis and for predicting treatment response (which may or may not be the same level). Efforts should be made to standardize investigations of NGAL in cirrhosis, focusing on consistent and inclusive definitions of ATN, as well as whether urinary NGAL should be normalized for urine creatinine. More work is needed to understand the value of NGAL around HRS‐AKI in patients with pre‐existing chronic kidney disease. There may also be a role for biomarkers like NGAL in predicting relapse of HRS, posttransplant recovery of kidney function (for better simultaneous kidney transplant allocation), and in predicting de novo future AKI in high‐risk ambulatory cirrhotic patients. Of course, one of the main barriers to bringing NGAL into mainstream clinical use is its availability. While used in Europe, it is not FDA approved for any indication in North America. In conclusion, this manuscript provides another independent cohort that validates NGAL's promise in the diagnosis and management of AKI and cirrhosis. Additionally, by demonstrating that NGAL can predict terlipressin response, this paper perhaps goes the furthest in rebutting the most common critique of urinary tubular biomarkers at‐large: "so what?" Many urinary biomarkers that correctly identify tubular injury have failed to make a clinical impact because of the lack of a subsequent intervention. With the FDA approval of telripressin, we may be able to use NGAL to direct a therapy that reverses HRS‐AKI more appropriately, using guideline definitions alone. As a community, we should seize this opportunity and work toward further defining the use of NGAL in AKI in cirrhosis.